Saturated and unsaturated 17-hydroxyandrostanes, their derivatives and substitution products and process of making same



Patented Apr. 24, 1945 SATURATED AND UNSA'EURATED 17-HY-DRQXYANDROSTANES, THEIR DERIVA- TIVES AND SUBSTITUTION PRODUCTS ANDPROCESS OF Karl Miescher, Riehen, and Albert Wettstein,

Basel, Switzerland, assignors to Ciba Pharmaceutical Products,Incorporated, Summit, N. 3., a corporation of New Jersey N Drawing.Original application December 26,

1940, Serial No.

371,833, new

Patent No.

2,311,067, dated February 16, 1943. Divided and this application October22, 1942, Serial No. 462,990. In Switzerland December 23, 1939 11Claims.

It has been found that aturated or unsaturated 1'7-hydroxy-androstanones, their derivatives (for example, esters orethers) or their substitution products with saturated or unsaturatedhydrocarbon radicals may be obtained by treating an androstane-l'l-one,containing in the rings A and B merely free or substituted tertiaryhydroxyl groups, with agents capable of transforming the group CO- intothe group CR(Ol-I)-, R representing hydrogen or a saturated orunsaturated hydrocarbon radical, causing the products thus obtained toreact with water, acid or alcohol eliminating agents in order toeliminate the free of substituted tertiary hydroxyl groups in rings A orB, hereupon treating with oxidising agents, and finally, if desired,further treating with hydrolysing and/or oxidising, dehydrogenating,water and acid elim inating agents. During this process, the 17 -carbinols may be converted if desired either during, before or after theelimination of the tertiary hydroxyl groups in rings A and B, into theiresters or ethers by the action of esterifying or etherifying agents.

The parent substances mentioned may be obtained, for example, by thedegradation of the side chain in correspondingdimethyl-cyclopentanopolyhydrophenanthrene compounds containing sidechains according to the description in patent application Serial No.371,058, filed Dec. 20, 1940 (now Patent No. 2,319,012, granted May 11,1943). They contain, particularly in the 5-position, or, for example, inthe 8-position, a, tertiary hydroxyl group which may also be esterifiedby inorganic or organic acids or may be etherified by phenols oralcohols.

Agents which are capable of transforming the C0- group into the -CR(OH)group, R having the meaning given above, are reducing agents in thewidest sense of the term, as well as, for example, metallo-hydrocarboncompounds, such as Grignard compounds, alkali-hydrocarbons and the like,which, in addition to the reduction of the l7-keto group, are capable ofintroducing in the same position an additional saturated or unsaturatedhydrocarbon radical, for example, a methyl, ethyl allyl, or acetylenegroup. The 1'7-carbinols thus obtained, particularly those containingsecondary alcohol groups, are, if desired, in this stage or only afterthe elimination of the tertiary hydroxyl groups, converted into theircorresponding esters or ethers in known manner by the action ofesterifying or etherifying agents. In this instance particular use ismade of esterifying agents which are capable of introducing aliphaticacid radicals, such as those of formic, acetic, propionic, noriso-butyric, nor iso-valeric, capric, caproic, palmitic, or stearicacids, as well as aromatic, fatty aromaticor inorganic acid radicals,for example, benzoic acid, cinnamic acid or substituted carbonic acidradicals. For the purpose of etherification, aliphatic oraliphatic-aromatic alcohols or phenols are introduced, for example,methyl, ethyl, benzyl alcohols, triaryl-methyl carbinols and the like.The products are now treated in known manner with water, alcohol or acideliminating agents, whereby, for example 4:5-or 5:6-

unsaturated compounds are formed.

Upon the unsaturated reaction products obtained oxidising agents are nowcaused to react, in particular those capabe of introducing oxygen orgroup containing oxygen in known manner in the a-position to the doublebond. For this purpose, as known for example, chromic acid, seleniumdioxide, or lead tetraacylates may be used, which lead to compoundscontaining oxo, hydroxy or substituted hydroxyl groups in the a-positionto the double bond. In place of these, however, oxidising agents mayalso be caused to react upon the unsaturated products which are capableof adding oxygen or groups containing oxygen directly or indirectly tothe double bond itself. For this purpose are suitable, for instance,peroxides, such as hydrogen peroxide, if desired, in the presence ofalkalis or metal oxides, furthermore per-acids, halogens, metal oxides,such as osmium tetroxide, if desired, in the presence of chlorates, alsopermanganates, lead tetracylates or halogen-silver benzoate complexes.In order to convert, for example, newly introduced epoxy groupings orsubstituted hydroxyl groups into free hydroxyl groups, the reactionproducts are further treated with hydrolysing agents, it being alsopossible, by cautious working, only partially to hydrolyse thesubstituents in rings 4 A or B but not the possibly substituted hydroxylgroup in the l'l-position. Therefore, in these cases, it is advantageousif the 17 -carbinol group has already been substituted by a difiieultlyhydrolysable radical.

In this way, compounds of the dimethyl-cyclopentanopolyhydrophenanthrene series have been obtained which contain afree, esterified or etherified hydroxyl group and furthermore, ifdesired, also a hydrocarbon radical in the l7-position, and whichcontain in rings A or B keto groups or free or esterified hydroxylgroups in the oc-DOSltlOI). to double bonds, or else two adjacent freeor esterified hydroxyl groups in rings A or B. From the compounds whichcontain hydroxyl groups, the desired ketones, saturated or unsaturated17-hydroxy-androstanones, their derivatives r substitution products, maysubsequently be obtained in a manner of itself known by the action ofagent which eliminate water or acid or by the action of oxidising ordehydrogenating agents. 7

The following scheme illustrates by means of formulae one of the abovereactions without in any way restricting it:

CH3 CH3 R HQC H3O s I/\/\/ r 1 1 l II CH3 CH1 R R H3O \J s 1130 i x/\i/\/ IV III \\I CH3 R $=free or substituted hydroxyl groups.R=hydrogen, saturated or unsaturated hydrocarbon radical.

. Example 1 v 1 part of 5-hydroxy-androstane-l'l-one of Formula I(a:=OI-I; prepared, for example, according to U. S. Patent No. 2,319,012by splitting the side chain in 5-hydroxy-cholestane) is hydrogenated in25 parts of pure alcohol by means of a nickel catalyst, prepared, forexample, according to the method of Rupe or Raney. After 1 molecule ofhydrogen has been absorbed, the hydrogenation is stopped, and thecatalyst is removed by filtration. The filtrate is then evaporated invacuo and the residue is dissolved in diisopropyl ether and allowed tocrystallise. In this manner, androstane-Bzl'I-diole is obtained ofFormula II (J:=OH; R=H). This compound is now heated for 2 hours withparts of boiling propionic acid anhydride, the secondary hydroxyl groupthus being acylated but the tertiary being split off as water. Thereaction mixture is then poured into water and, after the anhydride hasdecomposed, the ester which crystallises is filtered off at the pump,washed with water and dried in the vacuum exsiccator. Byrecrystallisation from hexane, A -androstene-1'7-ole-propionate isobtained in colourless crystals (Formula III;

=-OCO.C2H5; R=H), in addition to some A androstene-l'l-ole-propionate.

In place of a catalytic method, other reduction methods known to besuitable for the conversion of a keto group into a carbinol group may beused, for example, nascent hydrogen like an alkali metal and an alcohol,an organo-metal compound prone to the formation of unsaturatedhydrocarbons, like iso-propyl magnesium iodide, or even biochemical orelectrochemical methods. Instead of propionic acid anhydride, otherpropionylating agents may naturally be used, for instance, a propionicacid halide, or other esters or even ethers may be prepared.

In place of the radical of propionic acid, other ester or ether radicalsmay be introduced, for example those named before, or the new carbinolgroup may rest unprotected if suitable oxidising agents, for example,selenium dioxide, are chosen for the following oxidation.

Instead of eliminating the tertiary hydroxyl group during the acylationof the secondary hydroxyl, the elimination may be carried out before theacylation, for example, by means of an alcoholic solution of hydrogenhalide, or after the acylation has been carried out gently, for example,by means of propionic acid anhydride in pyridine at room temperature.

Instead of using 5-hydroxy-androstane-17-one as parent material, use maybe made of a compound having a substituted hydroxyl group, for example,an esterified or etherified hydroxyl, in the 5-position, for instance, aS-halogen-androstane-l'I-one. In this case agents which eliminate acidor alcohol, for example, alkalies or carbonic acid salts, are allowed toreact with the reaction product, thus obtaining the same end products.

If, in place of the 5-hydroxy-androstane-1'7- one, a parent material beused which is bydroxylated in another position, for instance, 8-hydroxy-androstane-17-one, its esters or ethers, the correspondingunsaturated product is obtained. I

Thus quite generally as intermediates androstane derivatives may beobtained containing in the rings A 'and B, for example in 5-position,merely free or substituted tertiary hydroxyl groups, which areeliminated later, and in 17- position a free, esterified or etherifiedhydroxyl group, for example, an acylated hydroxyl group.

1 part of this N-androstene-l7-ole-propionate described is dissolved in50 parts of glacial acetic acid, a solution of 1.2 parts of chromiumtrioxide in a little water is added and the whole is stirred at roomtemperature for 12 hours. 400 parts of water are now added and thereaction mixture is extracted exhaustively with ether; the etherealsolution is washed with bicarbonate solution and with water, is driedand then evaporated in vacuo. By fractional crystallisation, absorptionor sublimation, testosterone propionate (A-androstene-3-one-1'7--ole-propionate, of Formula V; .B=-OCOC2H5; R=H),together with the corresponding 6-oxoand 3:6-dioxo-compounds, isobtained from the residue.

In place of chromic acid, selenium dioxide or a lead tetraacylate, forexample, may be used for the oxidation. In this case, a A IS-hydroxyoracyloxy-androstene-l'l-ole-propionate of Formula IV is primarilyobtained, which subsequently, if necessary, after partial hydrolysis ofonly the 3-ester group, may also be converted into testosteronepropionate in a manner of itself known by the action of oxidising ordehydrogenating agents.

Example 2' A solution of excess of methyl-magnesium iodide in ether isdropped into a solution of 1 part of -chloro-androstane-17-one ofFormula I (prepared, for example, according to U. S. Patent No.2,319,012 by splitting the side chain in 5-chloro-cholestane). After thereaction has taken place, water and acid are cautiously added, theethereal solution is removed, washed and evaporated. The residue isheated to the boil for 1 hour with parts of methanolic caustic potashsolution of 5 per cent strength in order to obtain complete eliminationof hydrochloric acid from the 5-chloro-17-methyl-androstane-17- ole ofFormula II (:r=OI-I;Cl; R=CHs) which is formed as an intermediateproduct. The solution is poured into water, extracted with ether, theethereal solution is washed with water, dried and evaporated. A-1'7-methyl-androstene-17-ole of Formula III (.1:=OH; R=CH3) is obtainedfrom the residue.

In a completely analogous manner, compounds containing instead of amethyl other saturated or unsaturated hydrocarbon radical may beobtained, for example, the l7-ethyl-, 17-ethinylorl'l-allyl-androstane-l'7-oles with free or substituted tertiary hydroxylgroups, for example in 5, 8 or 9-position by reaction with, for example,

ethyl, ethinyl or allyl magnesium halides on the correspondinglysubstituted androstane-l'l-ones.

By energetic action of esterifying or etherifying agents, for example,the new tertiary carbinol groups in 17-position may be converted intoester or ether groups in known manner.

extracted exhaustively with chloroform; the

chloroform solution is purified from the last traces of colloidal osmiumby means of an acid absorption agent and is then evaporated to dryness.The crude 1'7 -methyl-androstane-4:5: l7-triole is obtained from theresidue.

So quite generally as intermediates androstane derivatives may beobtained containing in the rings A and B, for example in 5-position,merely free or substituted tertiary hydroxyl groups, which areeliminated later, and in 17-position a free, esterified (like acylated)or etherified hydroxyl group and a hydrocarbon residue, like a methyl oran ethinyl group.

The A -17-methyl-androstene-17-ole, described above, is converteddirectly into 17-methyl-testosterone of Formula V (m=OI-I; R=CH3 in amanner fully analogous to that described in Example 1 for the Aandrostene-17-ole-propionate, for example, b means of chromic acid, orit may be converted into A -17-methyl-androstene- 3:17-diole or its3-monoesters (Formula IV), for example, by the action of seleniumdioxide or a lead tetraacylate. These may then, if necessary,

after hydrolysis, be converted also into l7-methyl- Instead of theintroduction of a keto or free or substituted hydroxyl group in theoz-DOSitiOIl to the double bond, two hydroxyl groups may also be addedat the latter. To this end, the,A -1'lmethyl-androstene-l'I-ole istreated, for example, in ethereal solution with an ethereal solution of1.1 equivalents of osmium tetroxide, allowing the reaction mixture tostand 5 days at room temperature, after which the solution is evaporatedcompletely at a bath temperature of 30 C. The residue is heated for 2hours with an aqueousalcoholic solution of sodium sulphite. For thereductive hydrolysis of the osmic acid ester other reducing agents, forexample, acid agents such as ascorbic acid, or formic acid, may also beused. The reduction mixture is poured into water and Instead of thedirect addition of two hydroxyl groups at the double bond, an oxide ringmay first of all be added or one or ,both of the hydroxyl groups insubstituted form, for example, in the acylated state, the reagentsalready described, for example, being used in a manner of itself knownfor this purpose. The oxide rings or substituted hydroxyl group maysubsequently be hydrolysed if desired, the latter either completely orpartially.

For the last stage of the process, an agent capable of eminiating wateris allowed to react upon the 17-methy1-androstane-4:5:1'7-trio1e. If thehydroxyl group or groups be present in the esterified form in the 4and/or 5-position, which, for example, is the case if peracetic acid, alead tetraacylate or a halogen-silver benzoate complex has been used forthe hydroxylation, then, instead of an agent eliminating water, an agenteliminating acid is used, for example, alkali, or zinc dust in toluene.In this manner 17-methyl-androstane- 4-one-l7-ole is obtained.

This application is a division of our application Serial No. 371,833filed December 26, 1940.

What we claim is: l

1. A process of the character described, which comprises the step ofreacting an androstane-17- one of the formula in the 17-position isconverted into the group ([JR(OH) R standing for a hydrocarbon radical.

2. A process of the character described, which comprises the steps ofreacting an androstane-l'lone of the formula I A B wherein rings A and Bcontain no further substituent, with a Grignard reagent and with aqueousacid, whereby the group (ij=o in the l'7-position is converted into thegroup (lJR(H) R standing for a hydrocarbon radical, and then dehydratingthe resultant product, whereby the HO-- group indicated in the aboveformula is eliminated and a double bond is introduced in lieu thereof.

3. A process of the character described, which comprises the steps ofreacting an androstanel'l-one of the formula CH5 CH3 AIBl R standing fora hydrocarbon radical, and then reacting the resultant product with analkali, whereby the esterified tertiary hydroxyl group is eliminated anda double bond is introduced in lieu thereof.

4. A process of the character described, which comprises the steps ofreacting an androstane- 1'7-one of the formula CH; CH:

to C3 01 with a hydrocarbon-substituted metal halide and with aqueousacid whereby the group is converted into the -r JR oH group, R standingfor a hydrocarbon radical, then reacting the resultant product with analkali, whereby the C1 is eliminated and a double bond is introduced inlieu thereof.

5. A process of the character described, which comprises the steps ofreacting an androstanel7-one of the formula CH3 CH3 with ahydrocarbon-substituted metal halide :and with aqueous acid whereby thegroup is converted into the -(l3 R(OH) group, R standing for ahydrocarbon radical, then dehydrating the resultant product, whereby'the OH in 5-position i eliminated and a double bond introduced in lieuthereof.

i 6. A process of the character described, which comprises thesteps ofreacting 5-chloro-androstane-1'7-one with a compound of the formulaR.MgI and with aqueous acid, treating the resultant5-chloro-17-R-androstane-l'7-ole with methanolic KOH, and then reactingthe resultant A -17-R-androstene-l7-ole with chromic acid, whereby17-R-testosterone is produced, R standing fora hydrocarbon group.

7. A process of the character described, which comprises the steps ofreacting 5-chloro-androstane-l'I-one with a compound of the formulaR.MgI and with aqueous acid, treating the resultant5-ch1oro-l'7-R-androstane-1'7-o1e with methanolic KOH, and then reactingthe resultant A -17-R-androstene-l7-o1e with selenium dioxide, whereby17-R-androstene-3,l7-diol is produced, R standing for a hydrocarbongroup.

8. A process of the character described, which comprises the steps ofreacting 5-chloro-androstane-l'T-one with methyl magnesium iodide andwith aqueous acid, treating the resultant 5- I wherein X represents amember of the group consisting of tertiary hydroxyl and a group whichupon hydrolysis is converted into tertiary hydroxyl, and R stands for ahydrocarbon radical.

10. A compound of the formula on, CH3

wherein X represents a memberof the group consisting of tertiaryhydroxyl and a group which upon hydrolysis is converted into tertiaryhydroxyl.

11. The 5-chloro-1'7-methylrandrostane-l'l-ole.

KARL MIESCHER. ALBERT WE'I'ISTEDI.

